We will attempt to identify sensitive cholinergic markers in the CSF and to develop provocative neuropharmacological tests which will detect early Senile Demetia of Alzheimers Type (SDAT). By using the most sensitive techniques presently available, we will monitor the level of several parameters of acetylcholine (ACh) metabolism in the lumbar cerebrospinal fluid (CSF) of SDAT patients and controls. These assays will include ACh and choline (Ch) levels and choline acetyltransferase (ChAc) and acetyl cholinesterase (AChE) activities. The molecular forms (isozymes) of AchE will be separated and studied by isoelectric focusing and gradient microsedimentation analysis. The Ch/ACh, ChAc/ACh and AChE/ACh ratios in CSF will be detemrined. In a parallel study of the same patients, using acute i.v. administration, the effect of physostigmine and scopolamine on short-term memory function will be tested. Plasma and CSF levels of physostigmine will be monitored by means of a new HPLC method developed in our laboratory. Physostigmine levels, ACh and Ch levels, AChE and ChAc activities and effects on cognitive function will be correlated. This study will be the first to combine quantitative CSF analysis with pharmacological provocative tests and to simultaneously monitor physostigmine plasma levels in SDAT patients and healthy elderly controls.